Chemotherapy for Mesothelioma

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					Chemotherapy for Mesothelioma




              Jeremy P. Steele MD FRCP
Consultant Medical Oncologist, St Bartholomew’s Hospital, London
                    Chair, Mesothelioma UK
              Randomized trials in MPM
•   Pre 2003: many Phase II trials (No level I or II evidence; Cisplatin
    and antofolates were most active single agents; Cisplatin/Gem was
    “consensus best”)
•   Post 2003: 3 Randomized trials (Level I/II evidence)
     –   1. 2003 (N = 448) International: Cisplatin +/- pemetrexed Vogelzang et al,
         JCO (MST 13 mos for 2 drug arm)
     –

     –   2. 2005 (N = 250) EORTC/NCIC : Cisplatin +/- Ralitrexed Van Meerbeeck et al,
         JCO (MST 11 mos for 2 drug arm)

     –   3. 2007 (N= 409) MRC: Active symptom control (ASC) v ASC + Vinorelbine v
         ASC + MVP Muers et al, (MST 7-9 mos)

     –   4. 2007 (N=108) NCI/Chicago: Cisplatin/Gem +/- bevacizumab Kindler et al,
         (MST 15 mos for 2 drug arm)
             Phase III Single-Blind Trial: Design
                                      R            Pemetrexed 500 mg/m2 IV over 10
                                      A
   Stratification by                  N            minutes followed 30 minutes later by
                                      D            Cisplatin 75 mg/m2 IV over 2 hours, on
    • PS, histology, sex,             O            Day 1 q 3 weeks* (n = 140)
      WBC, disease                    M
      measurability                   I
                                      Z            Cisplatin 75 mg/m2 IV over 2 hours, on
                                      A            Day 1 q 3 weeks* (n = 140)
    • Baseline
                                      T
      homocysteine level              I
                                      O        Statistical Plan
                                      N
                                               Primary endpoint: survival
                                               80% power to detect hazard ratio (HR) of 0.67
                                               (based on α = .05 level, 2-sided log-rank test)


*With dexamethasone 4 mg po bid (Days –1, 1, 2).
                    Pemetrexed + Cisplatin Versus Cisplatin
                           Updated Survival 2005

              1.0
              0.9                             Pem + Cisplatin (n=226)
              0.8                             Cisplatin (n=222)
              0.7                                                 pem/cis         cis
Survival(%)




              0.6                         Median Survival (months) 12.8           9.0
                                             -
              0.5
                                          Hazard Ratio                     0.74
                                          P-value                         0.003
              0.4
              0.3
              0.2
              0.1
              0.0
                    0      5     10      15            20           25              30
                                      Time (months)               Presented WCLC 2005
                      Lung Function by Treatment


               2.70        P/C
                                                         P = .006
                           C                  P = .034
               2.65
                                 NS
Capacity (L)




               2.60
   Vital




                      NS
               2.55

               2.50

               2.45

               2.40
                      0          2               4          6
                                      Cycle
             Phase III trials of Chemotherapy
               in Advanced Mesothelioma
•   Pre 2003: many Phase II trials (No level I or II evidence (MST 7-9 mo
    Cisplatin/Gem was “consensus best”)
•   Post 2003: Randomized trials (Level I/II evidence)
     – 2003 (N = 448) International: Cisplatin +/- pemetrexed

       Vogelzang et al, JCO (MST 13 mos for 2 drug arm)
     – 2005 (N = 250) EORTC/NCIC : Cisplatin +/- Ralitrexed Van

       Meerbeeck et al, JCO (MST 11 mos for 2 drug arm)
     – 2007 (N= 409) MRC: Active symptom control (ASC) v ASC +

       Vinorelbine v ASC + MVP Muers et al, (MST 7-9 mos)
       Phase III Trial of Cisplatin +/- Raltitrexed in
          Mesothelioma (EORTC/NCIC Study)

   •   250 patients enrolled between 11/99 and 1/03
   •   Cisplatin 80 mg/m2 Day 1 with or without randomly assigned
       raltitrexed 3 mg/m2 Day 1 q 3 weeks


                                  Cisplatin              Cisplatin +
          Outcome
                                  (n = 124)         Raltitrexed (n = 126)
Response rate (%)                     14                      24 (P = .056)
Median survival (months)             8.8                     11.4 (P=.048)
1-year overall survival (%)          39.6                             46.2
Grade 3/4 neutropenia
                                      8                                 16
(%)
                                              Van Meerbeeck JP et al. J Clin Oncol. Oct 1, 2005.
Van Meerbeeck, et al. J Clin Oncol 23(28), October 2005
                   Chemotherapy
             in Advanced Mesothelioma
•   Pre 2003: many Phase II trials (No level I or II evidence MST 7-9 mo)
•   Post 2003: Randomized trials (Level I/II evidence)
     – 2003 (N = 448) International: Cisplatin +/- pemetrexed

       Vogelzang et al, JCO (MST 13 mos)
     – 2005 (N = 250) EORTC/NCIC : Cisplatin +/- Ralitrexed Van

       Meerbeeck et al, JCO (MST 11 mos)
     – 2007 (N= 409) MRC: Active symptom control (ASC) v ASC +

       Vinorelbine v ASC + MVP Muers et al, (MST 7-9 mos)
 UK-MRC study: A feasibility study of active symptom
 control with or without chemotherapy in malignant
                pleural mesothelioma


               Muers et al. Lancet. 2008;371:1685-94.




Based on the now arguable 2002 BTS recommendation of active symptom
                control as the standard of care in MPM:

“not known whether the addition of chemotherapy prolongs survival or
       provides worthwhile palliation with acceptable toxicity”
MRC Study: Design

  R
                    Active Symptom Control (ASC) only
  A
  N
  D
  O                 ASC + MVP (mitomycin, vinblastine,
  M                 cisplatin) q3w x 4
  I
  Z
  E
                    ASC + Vinorelbine Q3w until PD,
                    toxicity or refusal
                     Sample size
 • To detect an improvement of 3 months median survival
   (from 9 months with ASC to 12 months with ASC+MVP
   or ASC+V)

 • Required 840 pts/768 events over 4 yrs (90% power, 5%
   significance level)

• Feb 2005 – slow accrual
• Changed to a 2-arm comparison: ASC vs ASC+chemotherapy (but
  kept the 3-arm randomisation)
• Required 380 events (76% power, 5% significance level)

  Target of 420 patients (140 ASC vs 280 ASC+CT)
1.00       Overall Survival (ASC vs ASC+CT)
                                                        ASC              ASC+CT
                             Patients                   136              273
                             Deaths                     117              232
0.75




                             Median                     7.6 mos          8.5 mos
                             1 year survival            30%              37%
0.50




                             Hazard ratio = 0.89 (0.72, 1.12) p= 0.32
0.25
0.00




       0     6   12    18     24        30         36         42      48         54   60
                               T i m e ( m o n th s)

                      A SC alone                A S C + C h e m o th e r a p y
               Overall survival (3 arms)
1.00




                                                       ASC      ASC+MVP    ASC+V
                                        Patient        136      137        136
                                        Deaths         117      114        118
0.75




                                        Median         7.6 m    7.8 m      9.4 m
                                        1 year         30%      31%        42%
0.50




                                        HR                   0.98           0.81
                                        95%CI              [0.76,1.28]   [0.63,1.05]
                                        p                    p=0.91         p=0.11
0.25
0.00




       0   6   12   18       24        30         36       42      48     54      60
                              T i m e ( m o n th s )

                         A S C alon e                   ASC + MVP
                         ASC + N
      Summary of ASC vs Chemotherapy

• The chemotherapy arms of this study yielded median
  survivals of 7-9 months which is virtually identical to the
  cisplatin control arm of the cisplatin+pemetrexed study.

• While the addition of vinorelbine or MVP chemotherapy
  did not improve survival compared with ASC alone, a
  trial of cisplatin plus pemetrexed or gemcitabine
  compared to ASC alone, could be done for those who
  continue to believe that there is no role for
  chemotherapy in MPM
       What is the way forward clinically?

1) Develop new agents
   •   “Window of opportunity” phase II trials with pem
       + cisplatin as salvage/backup
   •   2nd /3rd line trials


2) Phase II trials of triplets (pemetrexed + cisplatin
   + new agent) leading to phase III trials
  A randomised trial in malignant mesothelioma (M) of early
  (E) versus delayed (D) chemotherapy in symptomatically
  stable patients: the MED trial. O’Brien et al.
Patients had a performance status<or=2, life expectancy>3 months and had stable symptoms for at least 4 weeks prior to 
randomisation. Patients were randomised to receive immediate chemotherapy or initial BSC with the addition of chemotherapy at 
time of symptomatic progression. 

All patients received the same platinum‐based chemotherapy regimen, for up to six cycles. 

RESULTS: 
43 patients were recruited, of which 21 were randomised to the early treatment group and 22 to the delayed treatment group. 

All 21 patients in the early group received chemotherapy versus 17 patients in the delayed group. 

Median survival was 14 months (1‐year survival 66%) for the early group compared with 10 months (1‐year survival 36%) for the 
delayed group (P=0.1). 

Quality of life was in general better maintained for early treatment and the health resources use was similar in both arms. 

CONCLUSIONS: In this patient group, presenting with stable symptoms after control of pleural effusion, the 
early use of chemotherapy provided an extended period of symptom control, and in this small trial a trend to 
survival advantage.

Ann Oncol. 2006 Feb;17(2):270‐5. Epub 2005 Nov 29
                   Recent 1st line Phase II studies of
                   Novel Doublets in advanced MPM

Drug combination                       N      RR         Author/Ref

Irinotecan/Gem                         15     14%    Ferrari, ASCO 2002

Oxaliplatin/Gem                       29      8%     Xanthopoulos 2008

Bevacizumab/erlotinib                 24      0%     Jackman, 2008

Cisplatin/Gem + MMM                   53      29%    Pinto, ASCO 2003

Caelyx/carboplatin/Gem                47      38%    Hillerdal, ASCO 2003

Epirubicin/Gem-NCTG                   68      13%    Okuno, Cancer 2008

Sorafenib/ Dox phase I                NA      1 PR   Richley 2006
   Develop New Agents with “window of
      opportunity” Phase II Trials?


• New agents worthy of study: proteosome inhibitors,
  apoptosis inducing agents. Celecoxib, cetuximab etc.


• Phase I/II trials in mesothelioma continue to be
  needed
              DAC Inhibitors in Mesothelioma:
                    Preclinical Studies

• Sodium Butyrate can lower the level of anti-apoptotic gene and
  protein BCL-XL in mesothelioma cells and mediate cell death (Cao et
  al Am J Respir Cell Mol Biol 2001)
• Sub-apoptotic doses of the HDAC inhibitor
  suberohydroxamic acid (SBHA) sensitizes MM cells to
  TRAIL apoptosis (Neuzil et al Biochem Biophy Res
  Communic 2004)
• Sequential treatment of mesothelioma cells by 5-Aza-2 deoxycytidine
  and depsipeptide induces apoptosis preferentially in cancer cells
  (Weiser et al J Immunother 2001)
• LBH589 is a potent inhibitor of mesothelioma cell lines at physiologic
  levels and valproic acid induces cell growth inhibition after long term
  incubation at supra-physiologic levels (Symanowski JTO 2009)
Suberoylanilide Hydroxamic Acid (SAHA, Vorinostat)

    13 patients with advanced mesothelioma enrolled on phase I
    study of oral SAHA
    11 received 300 mg BID × 3 days/week and 2 had 400 mg BID
    x 3 days/week
    Epithelioid 69%, mixed 23%, NOS 8%
    Prior chemotherapy regimens
             0      1 patient
             1      8 patients
             2      2 patients
             3      1 patients
             5      1 patients
    2 unconfirmed partial responses and 4 patients with prolonged
    stable disease
                           Kelly et al, JCO 2005; Krug et al, Clin Lung Ca, 2006
       Vorinostat Phase III Trial Design

Unresectable MPM                      R
One or two prior chemo                A        Vorinostat 300mg BID
regimens (most recent must            N        for 3 days q 7
include pem)                          D
                                      O
Stratify by:                                   or
                                      M
         Histology                    I
         KPS                          Z        Placebo
         # prior regimens             E


    Primary endpoint: Overall survival, N=660 patients
    1st interim analysis after 50 pts enrolled for response
    2nd interim analysis after 220 pts enrolled for secondary endpoints

    Correlative studies: tissue collection for genotyping, volumetrics, serial PFTs,
    symptom and QOL assessment
    NCI/Chicago Phase II Mesothelioma Study of
      Gemcitabine/Cisplatin ± Bevacizumab
                             R         gemcitabine/cisplatin plus bevacizumab
                             A         gemcitabine 1250 mg/m2 Days 1, 8 cisplatin 75
                             N           mg/m2 Day 1 bevacizumab 15 mg/kg Day 1
                             D              every 3 weeks, 6 cycles, bev until PD
                             O
Stratification by            M
-histology                   I
                             Z            gemcitabine/cisplatin plus placebo
-perf status (PS)            A         gemcitabine 1250 mg/m2 Days 1, 8 cisplatin 75
                                                 mg/m2 Day 1placebo Day 1
                             T
                                          every 3 weeks, 6 cycles, Placebo until PD
                             I
                             O
                             N

                    Accrual goal (n) ⇒ 106
 Randomised Phase II trial of gemcitabine/cisplatin
    +/- anti VEGF in Malignant Mesothelioma

Multicenter, double-blind placebo-controlled randomized trial, N=108 Primary
endpoint: TTP; Unresectable, chemonaive, histologically-confirmed MM

Study arms were well balanced
882 cycles administered (range 1-39; median 6-7)

Statistically significant increase in Grade 1 & 2 toxicities of alopecia, epistaxis,
hypertension, infections, proteinuria & stomatitis in bev arm. Grade 3/4 toxicities were
not statistically greater for CGB

1 yr survival 57%,
Median survival = 15 months


                                        Kindler et al. Proc ASCO 23 (16S) 2005 (abstr 7019)
Overall survival

           Bevacizumab 15.6 mo
           Placebo     14.7 mo

             Log rank p=0.91
Overall survival by baseline VEGF level

                                   VEGF ≤ Median
                                   VEGF > Median


                                    Logrank p=0.014




   Median VEGF level = 144 pg/ml
Overall survival by treatment: VEGF > median

                            Bevacizumab
                            Placebo

                             Logrank p=0.90
Overall survival by treatment: VEGF < median


                               Bevacizumab
                               Placebo

                               Logrank p=0.028
        Phase I/II Trials of New Agents in Mesothelioma

Chemotherapy/Group          No. Patients   Response   Survival
                              (Year)         Rate     (months)
Imatinib/Chicago             17 (2004)       0%          12
Erlotinib/SWOG                64 (2004)      0%           7
Gefitinib/CALGB              43 (2004)       4%           7
Capecitabine/CALGB           26 (2004)       4%          5

                             40 (2007)       8%         6.6
Vatalanib PTK 787/CALGB
                             38 (2008)       15%        9.0
Sunitunib/Australia


Thalidomide/ Netherlands     40 (2005)       0%         7.5
Dasatinib-src inhibitor      Open 2007       NA         NA
Everolimus/SWOG              Open 2009       NA         NA
L-alanosine                  16 2009         0%         0%

SSP-1 Immunotoxin            20/phase 1     10%         NA
Anti-mesothelin-MORab 009    13/ phase 1    All SD      NA
Conclusions about Gem/Cis/Bevacizumab


• In MPM, as in NSCLC, doublet chemotherapy
  regimens (platinating agent + anti-metabolite ie
  Gem/Cis) are likely to be equivalent to each other
  (e.g. Pem/Cis).

• The striking survival of the bevacizumab-treated
  patients with low VEGF levels lends support to
  initiating a study of pemetrexed/cisplatin +/-
  bevacizumab stratified by VEGF baseline levels
       Where do we go in meso clinical trials:
       Develop other 2-drug combinations?

• In NSCLC, Phase III doublet vs doublet trials always
  show equivalence
• Oxaliplatin/Gem promising in two phase II trials, thus
  oxaliplatin/Pem is planned
• Pemetrexed/gemcitabine not apparently better than
  single agent pem [Janne et al. ASCO 2004: PR= 9/49
  (20.0%), CR= 0,Median TTP = 4.3 mos, MST= NA]
     Chemotherapy for MPM – Conclusions
• Pemetrexed/cisplatin with folic acid and vitamin B12
  supplementation remains the standard of care for
  unresectable mesothelioma.
• It is unlikely that other doublets are superior (i.e
  gemcitabine/cisplatin).
• They are likely to be equivalent
• Trials of new agents in the second and third line setting are
  needed
• Early data with some newer agents (except DACs) are not
  promising yet
• Mesothelioma should no longer be considered a
  chemotherapy-refractory disease
jeremy.steele@bartsandthelondon.nhs.uk




                                         Kanchenjunga

				
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